A large variety of dosage forms for oral ingestion are known and readily available in the medical field. The most common of these is the tablet. The main limitations of pharmaceutical tablets include poor patient compliance due to difficulty in swallowing and lack of bioavailability of the active through ineffective dissolution of the tablet.
Fast-dissolving dosage forms (FDDFs) are convenient to use and are often used to address issues of patient compliance. There are many forms of FDDFs, for example, “soft” compressed tablets comprising a large amount of wicking/disintegrating agents, tablets comprising a large amount of effervescent agents, and lyophilized tablets. Most commonly, lyophilized, fast dissolving dosage forms, which are designed to release the active ingredient in the oral cavity, are formulated using rapidly soluble gelatin-based matrices. These dosage forms are well known and can be used to deliver a wide range of drugs. Most fast dissolving dosage forms utilize gelatin and mannitol as carriers or matrix forming agents. (Seagar, H., “Drug-Delivery Products and Zydis Fast Dissolving Dosage Form,” J. Pharm. Pharmaco, vol. 50, p. 375-382 (1998)). Typically, gelatin is used to give sufficient strength to the dosage form to prevent breakage during removal from packaging, but once placed in the mouth, the gelatin allows immediate dissolution of the dosage form. During processing, dosed solution/suspension is preferably frozen by passing through a gaseous medium. This serves to immobilize the solution/suspension rapidly, thereby improving the manufacture efficiency.
Lyophilized dosage forms can be altered by manipulating the amount and type of the structure forming agent in the formulation, most commonly gelatin. However, it has been found that such manipulations tend to upset the delicate balance of viscosity, acceptable dosing temperatures, susceptibility to microbial growth during dosing, and unit disintegration times. These are all critical to obtaining a commercially viable FDDF.
FDDFs manufactured by the freeze drying process such as the Zydis® dosage form are often preferred. They have the distinct advantages of a faster disintegrating time (i.e., less than 5 seconds, as opposed to 1 minute for the loosely compressed tablets), smoother mouth feel (i.e., free of the grittiness associated with the high wicking agents in the compressed tablets), improved pregastric absorption (thereby reduced side effects for certain medications), and increased storage options.
Hydrolyzed mammalian gelatin is often the matrix forming agent of choice in FDDFs because it gels rapidly upon cooling. However, there are problems with using gelling matrix forming agents with the manufacture of biological products or other products where a reduced dosing temperature is desirable to maintain the biological, physical and chemical stability during processing. With products having these characteristics, a matrix forming agent that is not prone to gelling when cooled is selected, such as non-gelling fish gelatin and pullulan, as disclosed in WO 00/61117 and WO 00/50013. However, there are other problems associated with using a non-gelling matrix forming agent. Formulations containing these non-gelling agents typically are not robust and lead to surface deformations when passing through the gaseous cooling medium during freezing. These surface deformations appear as cracks, agglomerates or nodules, and often affect patient compliance. Therefore, there is a need to devise a process that would combine the advantages of both gelling and non-gelling matrix forming agents.
Currently, there is also a need for manufacturing combination pharmaceutical products in FDDFs. In recent years, combination pharmaceutical products have become increasingly popular to treat multiple disease states or the same disease with reduced side effects. Recently launched combination products include: Symbyax® for bipolar depression from Eli Lilly; Lotrel® for hypertension from Novartis; and Caduet® for cardiovascular from Pfizer. However, combination products as FDDFs have been difficult to effectively manufacture, partly because of the typical manufacturing steps of FDDF, i.e., where an aqueous solution/suspension must be prepared and then dosed into preformed blisters before freeze drying. This aqueous solution/suspension must be chemically and morphologically stable throughout the dosing process, which can be problematic for the development of combination products. Therefore, there is a need to manufacture a lyophilized FDDF which controls and effectively eliminates inherent incompatibility of certain active ingredients used in the dosage form.
What is more, an FDDF which controls and effectively eliminates incompatibility between active ingredients and excipients and between multiple excipients during formulation of lyophilized FDDFs would be desirable. For example, preferred flavoring, sweetening, coloring, and buffering systems may be incompatible with active solutions. With regard to excipients, an effervescent couple consisting of citric acid and sodium bicarbonate can not be formulated as an aqueous unitary solution/suspension, but may be preferred in formulating an FDDF system with enhanced drug absorption.
There is also a need for an FDDF that can incorporate multiparticular active pharmaceutical ingredients with or without modified release coating. In particular, a combination of different release profiles, i.e., immediate release and extended release, in one FDDF would be desirable.
U.S. Pat. No. 5,039,540 teaches a method of manufacturing a carrier material having sufficient rigidity for carrying and administering of an active material selected from the group consisting of drugs, nutrients, vitamins, biologically active compounds, foodstuffs, and combinations thereof. This invention has limited applications, as very few pharmaceutically active materials are immiscible in the organic solvent that is used in the pharmaceutical processing. If the active material is even slightly soluble in the organic solvent, the active material would be extracted during the dehydration process, thereby compromising the dose uniformity of the finished products. Further, this reference specifically indicates that the disclosed invention has little similarity to the process of lyophilization.
WO 2004/066924 discloses a pharmaceutical dosage form comprising at least two layers whereby a proton pump inhibitor is in one distinct layer and an aluminum, magnesium or calcium antacid salt is in a second distinct layer. The dosage form can be chewable or rapidly disintegrating. There is no mention of the process of manufacturing a lyophilized FDDF that can disintegrate in the oral cavity. Further, there is no disclosure of manufacture of an FDDF through the sequential dosing of separate solutions/suspensions.
WO 2006/063189 discloses a multi-layered drug delivery system containing at least one gum layer and at least one rapidly dissolving tablet layer. The tablet layer contains a therapeutically effective amount of a medicament which is susceptible to rupture upon chewing, thereby causing release of the drug. There is no disclosure of an FDDF incorporating multiple and sequentially dosed layers.
The present disclosure uses a combination of at least two formulations, one containing a gelling matrix forming agent and the other containing a non-gelling matrix forming agent, which are sequentially dosed in layers to optimize and expand the uses of FDDF to new and potentially previously incompatible agents and to more effective packaging. This is a significant advancement in the state of the art.